Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors.

Abstract

Previously, we developed a strategy to develop a novel class of histone deacetylase (HDAC) inhibitors by tethering short-chain fatty acids with Zn(2+)-chelating motifs, which led to N-hydroxy-4-(4-phenylbutyryl-amino)benzamide (HTPB), a hydroxamate-tethered phenylbutyrate derivative with sub-micromolar potency in inhibiting HDAC activity and cancer cell proliferation. In this study, we carried out structure-based optimization of HTPB by using the framework generated by the structure of histone deacetylase-like protein (HDLP)-trichostatin A (TSA) complexes. Docking of HTPB into the HDLP binding domain suggested that the hydrophobic microenvironment encompassed by Phe-198 and Phe-200 could be exploited for structural optimization. This premise was corroborated by the greater potency of (S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide [(S)-11] (IC(50) in HDAC inhibition, 16 nM), of which the isopropyl moiety was favorable in interacting with this hydrophobic motif. (S)-11 at concentrations as low as 0.1 microM was effective in causing histone hyperacetylation and p21(WAF/CIP1) overexpression and suppressing proliferation in cancer cells.

• Authors: Qiang Lu, Da-Sheng Wang, Chang-Shi Chen, Yuan-Dong Hu, Ching-Shih Chen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 17 Pg. 5530-5 (Aug 25 2005) ISSN: 0022-2623 [Print] United States
• PMID: 16107152 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzamides
• CDKN1A protein, human
• Cell Cycle Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Histone Deacetylase Inhibitors
• Histones
• Hydroxamic Acids
• N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)benzamide
• N-hydroxy-4-(4-phenylbutyrylamino)benzamide
• Phenylbutyrates
• trichostatin A
• Histone Deacetylases

Topics

• Acetylation
• Benzamides (chemistry)
• Cell Cycle Proteins (biosynthesis)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21
• Histone Deacetylase Inhibitors
• Histone Deacetylases (chemistry)
• Histones (metabolism)
• Humans
• Hydroxamic Acids (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Phenylbutyrates (chemical synthesis, chemistry, pharmacology)
• Quantitative Structure-Activity Relationship
• Stereoisomerism